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Friday, October 26, 2012

The Mipomersen Briefing Docs: Gymnotic Delivery Revealed

After Alnylam’s CEO John Maraganore famously failed to
deliver on his Big Pharma platform partnership promise in 2009 (aka ‘SRTL’), and ISIS Pharmaceuticals announced a preferred partnership with
GSK in March 2010, it seemed that Dr. Maraganore salesmanship was outdone by
one of the best biotech salesmen ever: Dr. Stanley Crooke.

In addition to likely having deprived Alnylam of a deal, what is this salesmanship claim based on? It is the fact that not all that long ago, antisense technology had fallen out of favor in Big
Pharma. This was because it required large amounts of oligonucleotides and, partly as a result of that, was associated with non-specific
immunostimulatory effects. And this is where the more elegant RNAi Therapeutics was supposed to take over. Despite this poor track record, the technology managed a comeback, ironically partly on the back of RNAi Therapeutics which was seen stumbling at the ‘delivery’ stage. In some cases out of the frustration of making RNAi delivery work, the 'naked' delivery approach of antisense would be embraced by the likes of GSK,
BiogenIdec, Pfizer, Genzyme, and VCs making the application of Santaris' LNA
technology the basis of start-up biotechs targeting emerging classes of
non-coding RNAs such as microRNAs or long non-coding RNAs.

The reason, however, why I had always favored RNAi as the more ‘natural’ gene
silencing modality over antisense is that antisense, to this day, relies on achieving extremely high steady-state tissue concentrations (>100-300mg/kg
of liver and kidney tissue e.g., see ISIS TTR patent application US2011/0294868) either by using reactive/sticky chemistries such
as the phosphorotioate backbone or more gentle backbones such as the morpholino
chemistry that, however, require even larger amounts of oligonucleotides.

Mipomersen Briefing Docs Surprises

Unfortunately, the publication last week of the FDA Briefing Document related to the new drug application (NDA) for Mipomersen (tradename: KYNAMRO) by ISIS and partner Genzyme, should serve as a
reminder that giving an old technology new names such as ‘gymnotic’ or saying that the algorithms now allow for the discovery of
much more potent antisense sequences without any new chemistry (despite the fact that narrow tiling had always been practiced) are telltale signs that
the biggest change that has occurred was in the marketing department.

The selective disclosure strategy by ISIS
Pharmaceuticals on mipomersen has certainly contributed to the impression that antisense
technology had indeed made important progress. Dr.
Crooke claimed in a recent interview on Mad Money with Jim Cramer that ISIS had been very transparent with mipomersen. I could agree that there has been a lot
of scientific data released on mipomersen by ISIS and
their clinical investigators, but in hindsight this was arguably not for the claimed sake of transparency, but for providing the impression that mipomersen was a
safer drug than it probably is.

Here are a few examples of the ‘surprises’ that were revealed
in the Briefing Docs:

1) Liver Fat: More and Persistent

While the significance of the non-alcohol-related
accumulation of fats in the liver in predisposing towards liver fibrosis is still
hotly debated among experts, ISIS tried to dispel the still understandable fears about ApoB-knockdown-related fat
accumulation in the liver by claiming a) that it was only modest, and b) that feedback mechanisms allowed the liver
to adjust and that liver fat would decrease over time. Supporting the impression that ISIS was
concerned about transparency was the publication (Visser et al. 2010) of liver fat data from a 13-week study in a small, 21-patient study population which only showed a trend of such accumulation (median control-adjusted increase from baseline to day 99 of < 1%).

Compare that to the actual results (as revealed in the
Briefing Docs): In study ISIS301012-CS7 and CS12, 61.8% (63/102) in the mipomersen group had a >5% increase in hepatic fat content. This already shows that the median
increase is definitely higher than 5%, not < 1%. Moreover, in study CS6, 16% had average liver fat of > 20%
measured at least once. 30-40%
liver fat contents also were not uncommon.
Such values were practically not observed at baseline or in control
subjects despite ISIS’ repeated claims that
such values are of no concern since NAFLD is so common anyway.

Furthermore, the data such as capture in Figure 10 of the Briefing Document show
that there is no basis for claiming that the liver adapts and liver fat
contents come down over time. They only
come down after you discontinue treatment.

Suggesting that the fat accumulations could be of clinical
significance, a fibrosis-related biomarker score (ELF) was elevated in the
mipomersen population.

To be clear, at least the liver fat accumulations (not
sure about the ELF score) is very likely
a target-related side effect and cannot be attributed to the phosphorothioate antisense platform per se, but it is an important issue for mipomersen and raises suspicions about the way ISIS Pharmaceuticals has dealt publicly with platform-related safety issues.

2) Partial Clinical
Hold: Vasculitis

Were you surprised by the fact that, according to the Briefing Doc, the FDA issued a Partial Clinical Hold for the non-severe LDL patient population in January
2008? I certainly was taken by surprise and would also think that this should have been disclosed in an SEC filing as a Partial Clinical
Hold for your lead program should be considered a material event. Not only can shareholders be pitied, but also Genzyme which less than a month before invested more than $300M in mipomersen! I cannot imagine that they would have closed such a deal had it known that there was data that would trigger such
a Hold (I do not exclude that the data was there under their nose, but in that case it was probably either buried under a
pile of paper, or Genzyme just did not do their job well).

Apparently (à Briefing Doc), the ‘final interim report’ from the
52-week monkey tox study that was submitted in June
2007 showed vasculitis (inflammation of the vasculature which can impair
blood supply and therefore organ function, possibly leading to organ failure) at clinically relevant doses
of 3mg/kg and up, mainly, but not exclusively, in the gastrointestinal tract. Although
the Hold was lifted after the actual clinical safety data did not indicate
vasculitis to be an issue, subsequent skin biopsies around the injection sites showed an
accumulation of inflammatory cells around the vasculature.

Although similar to the liver fat issue, the clinical significance and degree of systemic
vasculitis due to phosphorothioate oligonucleotides remains unknown in Man, the
potential for sustained inflammatory processes in the entire vasculature is a
serious safety concern that needs to be studied in more detail before the technology
can be applied to less than the most severe, 'orphan' patient populations- if at all.

3) Liver Enzyme
Increases

That mipomersen increased liver enzymes in the serum, a
measure of liver tox, has been widely known. But
ISIS used to claim that in a given individual these were
one-off findings that could just as well have come after a night of heavy
drinking. By contrast, it seemed to me new news that there were cases where elevated (>3x ULN) liver enzymes were
found on at least two subsequent investigations.
In fact, the FDA feels that the liver enzyme increases warrant them be tightly monitored as
part of a REMS program should mipomersen be approved in the homoFH population.

4) Injection-Site
Reactions and Discontinuations

One of the major marketing tools, and in fact actual draws,
of ‘gymnotic delivery’ has been that
it can be subcutaneously administered, while the leading RNAi Therapeutics
delivery technologies, foremost Tekmira’s SNALP, still rely on intravenous
infusion (for most applications at least). Turns
out that injection site reactions ranging from pain, redness, swelling, to skin
discolorations and haematomas were a major factor for study drug
discontinuations, especially in the open-label phases of the studies which should be indicative of what will happen in a real-world setting. Overall, 61% of HoFH patients (23 of 38)
discontinued study drug during the open-label phase, and 77 of 141 discontinued
in the pooled Phase 3 population (including non-hoFH subjects). Other
adverse events attributable to the inflammatory potential of the
technology, such as flu-like symptoms, contributed to the high discontinuation rate.

A curious, hitherto undisclosed finding, were injection site recall reactions with
mipomersen (but not control). This
refers to an inflammatory reaction at an old injection site when the drug was
administered at a new site. The
molecular basis and importance for such recall reactions seem unknown. In fact, my literature searches suggest that
they have almost exclusively been described for the TNF-alpha blocking antibody
Enbrel. However, to me, they once again
indicate the systemic inflammatory potential of phosphorothioate antisense
chemistry, likely involving adaptive immunity. Accordingly, 30/50 patients (60%) in the CS5
and 6 studies exhibited mipomersen antibodies compared to none in the control
population- another ‘surprise’ that should be applicable to the phosphorothioate
platform in general.

5) Carcinogenicity

While there were ~2-3x more cases of tumors in the
mipomersen-treated population compared to control, I agree with the reviewers
that they are not the basis for concluding that mipomersen increases the risk of
developing cancer. This is because of
the nature of the reported cases and the relatively short treatment duration
after which many of them occurred.

However, what would worry me more is that in the preclinical
carcinogenicity studies in rodents (mice and rats), mipomersen clearly
increased cancer risk- despite ISIS’ claim
that they have been ‘clean’. Among the
findings were hepatocellular adenoma and subcutaneous tumors. Having a report by your CRO stating the
findings are likely species-specific issues and not applicable to humans, does
not mean that the findings are not material in a regulatory sense, especially
as they were made during a period at the FDA when the agency was much more
risk-averse. I expect the clinical and preclinical
findings to cause carcinogenicity to be included in a REMS program.

6) Kidney Damage

The liver, spleen, and kidneys are the major sites of phosphorothioate
accumulations. Consequently, it is not
surprising that kidney damage has been an important safety concern of such antisense
technology. Although the clinical safety findings
did not demonstrate that mipomersen impaired kidney function, the study drug did
increase the amount of protein found in the urine (proteinuria). This finding supports that kidney function remains a safety
concern and such monitoring should be included in a REMS.

In summary, the safety findings were not all that surprising given what we know about phosphorothioate safety in animals and study discontinuations by competitor Santaris, very likely due to safety. However, if you indeed have taken the reassurances by ISIS CEO Dr. Crooke literally, you may be justified in feeling misled. Even on that count, however, I am not all that surprised, and his salesmanship may indeed be one of ISIS' great assets.

Disclosure: The author is 'long' the stock ($ISIS).

Clarification: The term 'gymnotic delivery' in the linked paper refers to a specific protocol for optimizing gene knockdown in tissue culture in the absence of assisted delivery. However, the term has been more broadly used by Santaris to refer to unassisted delivery in general (including clinical applications), obviously in an effort to express that in contrast to phosphorothioate oligonucleotides, RNAi needed assisted delivery. I found it suspect, however, that they used a new term to refer to an over decade-old industry practice. In a further clarification, I have not seen ISIS Pharmaceuticals adopt the term either. But clearly, not using (in most cases) assisted delivery has been a greatly exploited marketing tool of the antisense industry built on the back of RNAi Therapeutics.

Not sure about the dosage used in Regulus' drugs. Yes, if lower dosages translate into lower tissue concentrations and it is still active, then it could work indeed. It will be interesting to see how much tissue concentrations are required to inhibiting a microRNA as opposed to mRNA. Also, there is issue of chronic treatment vs transient treatment. If you think e.g. of miR-122 inhibition for the treatment of HCV, the risk of incurring some of the mipo-type issues should be much reduced.

What is your technical opinion on Antisense Therapeutics Ltd and their products ATL1101, ATL1103 and ATL1103. Do you envisage problems associated with mipo to be reflected in phase 11 and phase 111 trials of these products. Appeciate your response..

Dirk, great review of the facts around mipo. I'm a bit ashamed to say that I didn't fully appreciate the level of discontinuation within the mipo trials... Half dropped? That can't bode well for a repeat treatment, and 60% of the patients generated antibody reactions to the drug? I guess that's acceptable if you're treating a rattlesnake bite with horse anti venom, but a cholesterol lowering drug given for the remainder of their lives? And with competitors (PCSK9) out there, I can't see this getting much, if any, traction in the market.

In a similar vein, based on applicable data from either human or NHP data, would you be willing to rank the potential nucleic acid drugs in the works? We've seen so much fail with the hype and promise of both antisense and RNAi, it would be exceptionally helpful to have a review of the still-in-contention drugs out there, from preclinical to phase III. Obviously, there would need to be rankings for effectiveness, side effects, potential and probable market size, longevity of response etc. If you have the time, I think such a review would make a fantastic blog entry.

When phosphorothioates are used in RNAi triggers, it's typically in the overhang (2 modifications, one on each strand). To get the antisense-type PS pharmacology, and presumably tox, significantly more modifications than that required.

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